Major depression is the most common psychiatric disorder, affecting over 17% of individuals over the course of their lifetime. Genetic and environmental factors working in concert determine an individual's vulnerability to depression by affecting the use of genetic information in the brain. This use of genetic information can be measured as the amount of messenger RNA (mRNA) that is produced from a single gene, a process described as 'gene expression analysis'. [unreadable] In the proposed study we will use an animal model of depression, the forced swim test, to investigate the influence of environmental stress and chronic antidepressant treatment on gene expression in rat hippocampus. [unreadable] We hypothesize that resilience to depression occurs as a result of adaptive changes in the brain. We will observe these adaptive changes by large-scale gene expression analysis, using oligonucleotide microarrays and quantitative reverse transcription polymerase chain reaction (RT-PCR). We further hypothesize that animals show behavioral depression if and when these adaptive changes in gene expression fail to occur. [unreadable] We will also test the hypothesis that chronic treatment with antidepressant drugs works by facilitating this adaptive pattern of gene expression changes. [unreadable] This is a departure from the traditional way of thinking about depressive illness. The traditional view suggests that depressive illness occurs as a result of a change of metabolism or neuronal circuitry in the brain of affected subjects. We propose just the opposite: that stress resilience is accompanied by an adaptive change in brain neurochemistry that is missing in depressed individuals. Hence, depressed subjects resemble controls that have not been challenged with environmental stress. [unreadable] Our approach is novel because it focuses on investigating factors that protect the individual from depression, rather than on changes that occur as a result of the disease. If our hypothesis is true, it would mean a paradigm shift in our understanding of affective illness that could alter the focus of treatment from the current management of symptoms to their prevention [unreadable] [unreadable]